Abstract Filtered introduces students and teachers to the biological concepts and logical thinking skills used in the bioinformatics analysis of human and viral genomes. Bioinformatics employs computational tools to store, manage and query biological data, weaving together engineering, biology, computer science, statistics and mathematics. It is a key component of modern clinical research and patient care. Although bioinformatics concepts are often incorporated in high school life science courses, there is a lack of available educational resources to effectively address key learning targets. To fill this gap, the HudsonAlpha Institute for Biotechnology is developing a bioinformatics-based serious game called Filtered, which takes place during a pandemic. Played on a tablet, mobile device or through a web browser, students become entry-level bioinformaticians employed by a laboratory searching for genomic insights into a deadly virus and the small group of humans seemingly resistant to infection. Through gameplay, students are introduced to a series of core biological concepts, reinforced through bioinformatics tools that align DNA sequences, call genetic variants, compare sequences across evolutionary history, and determine the impact of sequence changes. A series of puzzles allows students to recognize the tool's purpose, strengths and weaknesses. Once students master the tools, they can appropriately classify the virus, identify human variants that confer resistance to infection, and propose a treatment option to halt the pandemic. Online written and multimedia materials support students and educators, and link the content to workforce opportunities in genome analysis and other aspects of bioinformatics. Educator resources include content primers and extensions, links to national and other standards, sample lesson plans, guides for classroom use, and suggested assessment strategies. Professional development includes pedagogical training in using Filtered as well as content-deepening sessions on bioinformatics, genome analysis and evolution. The implementation plan focuses on high school biology classrooms. Special emphasis is given to training educators who work with typically underrepresented populations, including students of African-American and/or Hispanic ethnicity as well as those in inner-city or rural areas. Filtered allows students to approach real-world problems using 21st century skills, pulling multiple lines of evidence from molecular biology, human genetics, population biology and evolution as they draw connections between their classroom lessons, personal interests and present-day applications.